In the United States, it is estimated that 8 million people suffer from peripheral artery disease (PAD). PAD is characterized by a gradual reduction in blood flow to the muscular arteries of the lower extremities caused by atherosclerosis. For those with severe PAD, lower extremity bypass grafting remains the predominant option for limb salvage. Although native vessels remain the gold standard conduit for bypass grafting, they are not available in approximately one-third of patients due to intrinsic venous disease or prior vein harvesting. In these cases, expanded polytetrafluoroethylene (ePTFE) grafts are the most commonly used alternative despite dismal patency rates due to the formation of thrombosis and neointimal hyperplasia. To address these problems, many researchers have been investigating alternative strategies that involve surface modification of the graft's lumen. However, approaches to date have met with limited success. Poly(1,8 octanediol citrate) (POC)-coated ePTFE grafts offer a potential alternative as they have been shown to be biocompatible, compliant, and have anti-thrombogenic properties in vitro and in vivo in a porcine animal model. Furthermore, POC can serve as a vehicle for the controlled release of drugs. A potential drug candidate, all-trans retinoic acid (ATRA), has been shown to inhibit smooth muscle cell proliferation and neointimal hyperplasia in several animal models as well as induce antithrombotic genes and upregulate nitric oxide in vascular endothelial cells. The objective of this proposal is to develop a biocompatible, non- thrombogenic POC-ePTFE vascular graft that can release, in a controlled manner, ATRA and assess whether the controlled release of this small molecule can reduce neointimal hyperplasia and thrombosis. Toward this goal, the specific aims are to a) fabricate non-thrombogenic ATRA-eluting POC-ePTFE grafts with varying release rates and b) assess the effect of the controlled release of ATRA on thrombosis and neointimal hyperplasia in a carotid artery ePTFE porcine bypass model. In particular, POC-ePTFE grafts will be loaded with ATRA by swelling in solvent, and release will be modulated by varying polymerization conditions to control the degree of swelling and degradation rate. Grafts that show controlled release and an effect on smooth muscle and endothelial cells in vitro, will be implanted in a porcine carotid artery bypass model to assess inflammation, thrombosis, and neointimal hyperplasia. Successful completion of this Phase I application will demonstrate feasibility of our concept by developing a novel prototype that can be tested in patients in a Phase II proposal. In summary, we feel that our innovative product will ultimately have a significant impact on the care of patients with vascular disease. PUBLIC HEALTH RELEVANCE: Expanded polytetrafluoroethylene (ePTFE) grafts used to treat severe peripheral artery disease have dismal patency rates due to blood clotting and overgrowth of cells leading to occlusion and graft failure. Poly(1,8-octanediol citrate) (POC) polymer coated ePTFE grafts have the potential to improve patency rates as they have demonstrated reduced clotting compared to bare ePTFE and can release drugs in a controlled manner to prevent the overgrowth of cells. VesselTek Biomedical aims to create controlled drug release POC- ePTFE vascular grafts to improve the patency of bypass grafts and reduce the incidence of limb amputation caused by severe peripheral artery disease.